All of these receptors are G-protein-coupled receptors with a high degree of amino
acid sequence homology amongst them. On pharmacological grounds, there appears to
be multiple subtypes of each receptor:μ 1 ,μ 2 ,δ 1 ,δ 2 ,κ 1 ,κ 2 ,κ 3.
5.18.4 Enkephalinergic PathwaysThe many actions of enkephalin opiate peptides notwithstanding, the principal interest
of medicinal chemists is still the analgesic effect of opiate alkaloids and their analogs.
An understanding of pain and the central pain pathways is therefore essential to the
study of these agents, and the distinction between pain and pain perception must be
made. There is a considerable personal and psychological component involved in this
phenomenon, aptly called the “puzzle of pain.” Two major pathways are involved: the
first is the neospinothalamicpath that mediates sharp localized pain; the second is the
paleospinothalamicpath involved in the dull, burning pain that responds well to opiates.
The dorsal horn of the spinal cord is involved in collecting the nociceptive(pain) stim-
uli. However, these stimuli are experienced by cortical centers and interpreted emo-
tionally by the limbic system. The distribution of enkephalin opiate receptors along
these pathways has been demonstrated, and the intracerebral or epidural injection of
opiates in very small doses can produce long-lasting analgesia. Electrical stimulation of
the central and periventricular gray matter within the brain leads to the same effect.
There are many peripheral organs that possess enkephalin opiate receptors: the ileum,
the most distal part of the small intestine, and the vas deferensare the most significant.
The receptors in the ileum are responsible for the antidiarrheal activity of opiates. This
is also the explanation for the severe constipation that may occur when people use
opiates for pain relief.
5.18.5 Physiological Effects of Opiate HormonesThe principal opiate effect in mammals is analgesia—the reduction of pain perception.
The endogenous peptides probably also modulate dopaminergic and cholinergic centers
in the brain. Most opiates have a number of undesirable side effects. First and foremost
are the addictive narcotic effects: euphoria and sedation in humans, apes, and dogs;
excitation, fright, or convulsions in cats, cattle, and horses. It might be argued that seda-
tion and euphoria are useful components rather than undesirable effects in alleviating the
anxiety that accompanies pain. Indeed, high doses of morphine cause a deep narcosis.
Another dangerous side effect is respiratory depression, which involves a decrease in
the CO 2 sensitivity of the respiratory center, causing CO 2 retention and cerebral vasodi-
lation. This is the potential cause of death when opiates are overdosed. Some humans
suffer from nausea and emesis upon morphine administration.
Withdrawal symptomsare experienced when exogenous opiate agonists are abruptly
discontinued in persons dependent on or addicted to opiates. Dependence is a physio-
logical (as well as psychological) adaptive state. It varies with the particular drug, its
dosage, and the duration of addiction; the symptoms of abstinence may therefore also
vary in severity. These symptoms become manifest as a loss of appetite and weight,
mydriasis, chills and sweating, abdominal cramps, muscle spasms, tremor, and piloerec-
tion(“gooseflesh”—hence the slang “cold turkey” for opiate withdrawal symptoms).
HORMONES AND THEIR RECEPTORS 353